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Unusual effects of common antibiotics
A 60-year-old man is admitted for respiratory failure following a massive myocardial infarction. He develops ventilator-associated pneumonia and is treated with cefepime and vancomycin. Three days later, he develops prolonged atypical absence seizures.
What caused these seizures? The neurologist thinks it might be the cefepime. Do you agree?
Antibiotics are widely used in the United States, with 269 million courses of oral therapy prescribed in 2011.1 Adverse effects such as rash are well known, but rare effects such as seizure, hypoglycemia, and hypoxemia may not be immediately attributed to these drugs.
In this article, we review less-recognized but potentially serious adverse effects of antibiotics commonly prescribed in the United States. We have structured our discussion by organ system for ease of reference.
NERVOUS SYSTEM
The potential adverse effects of antibiotics on the nervous system range from encephalopathy and seizure to nonconvulsive status epilepticus.
Encephalopathy and seizure
Encephalopathy has been reported with penicillins, cephalosporins, sulfamethoxazole-trimethoprim, quinolones, and oxazolidinones such as linezolid.2,3
Seizures are known to occur with penicillins, cephalosporins, carbapenems, and quinolones.2–4 For cephalosporins, these effects are more common at higher doses, in elderly patients, and in patients with renal impairment. Carbapenems are associated with seizure activity in elderly patients.2–4
Encephalopathy and seizure can also occur on a continuum, as is the case with piperacillin-induced encephalopathy, with progressive dysarthria, tremor, and progressive confusion culminating in tonic-clonic seizures.2
Nonconvulsive status epilepticus
Nonconvulsive status epilepticus, marked by prolonged atypical absence seizures, has complicated the use of penicillins, quinolones, clarithromycin, and cephalosporins, specifically cefepime.2,3,5 Diagnosis can be difficult and requires clinical awareness and confirmation with electroencephalography.
Class-specific neurologic effects
Certain antibiotics have class-specific effects:
Tetracyclines: cranial nerve toxicity, neuromuscular blockade, and intracranial hypertension.2
Sulfamethoxazole-trimethoprim: tremors and psychosis, with visual and auditory hallucinations.6
Macrolides: dysequilibrium and potentially irreversible hearing loss.2
Quinolones: orofacial dyskinesia and a Tourette-like syndrome, with a higher incidence reported with newer quinolones.7
Linezolid: optic and peripheral neuropathy2; neuropathy can be persistent and can lead to loss of vision. The package insert recommends monitoring visual function in patients taking linezolid for more than 3 months and in any patient reporting visual symptoms.8
Linezolid is also associated with serotonin syndrome when combined with a drug that potentiates serotonergic activity, most commonly selective serotonin reuptake inhibitors. The syndrome is characterized by a triad of cognitive or behavioral changes, autonomic instability, and neuromuscular excitability such as spontaneous clonus.9
Metronidazole: optic and peripheral neuropathy, in addition to cerebellar toxicity and central nervous system lesions on magnetic resonance imaging of the brain. In a series of 11 cases of cerebellar toxicity, most patients presented with ataxia and dysarthria associated with high total doses of metronidazole, and in most cases, magnetic resonance imaging showed resolution of the lesions upon discontinuation of metronidazole.10
HEMATOLOGIC AND RHEUMATOLOGIC EFFECTS
Agranulocytosis has been associated with beta-lactams, in most cases with prolonged exposure. In one report, the average exposure before onset of agranulocytosis was 22 days for nafcillin and 25 days for penicillin. For penicillins, more than 50% of cases involved high daily doses.11
Likewise, most episodes of vancomycin-induced neutropenia were reported to occur after 20 days of therapy.12
In another study, most cases of drug-induced anemia were due to ceftriaxone and piperacillin.13
Drug-induced thrombocytopenia has been described with penicillins, cephalosporins, sulfonamides, and vancomycin14 and is a well-recognized effect of linezolid. The syndrome of drug reaction with eosinophilia and systemic symptoms, a severe and rare adverse reaction, has been reported with minocycline, sulfamethoxazole, and vancomycin.15
The tetracycline minocycline has been reported to cause drug-induced lupus and polyarteritis nodosa-like vasculitis.16 Drug-induced lupus presents as myalgias and arthralgias, serositis, constitutional symptoms, and positive antinuclear antibody titers. The effect is not dose-dependent. Penicillin, cefuroxime, and nitrofurantoin have also been implicated.16
Kermani et al17 described 9 cases of polyarteritis nodosa, in which 5 patients (56%) had systemic involvement including renal artery microaneurysm, mononeuritis multiplex, and mesenteric vasculitis, and some of these patients also had cutaneous involvement. All patients had positive antineutrophil cytoplasmic antibody in a perinuclear pattern. The median time from start of the minocycline to symptom onset was 9 months, and the median duration of use was 2 years.
Quinolones have also been reported to cause fatal hypersensitivity vasculitis.18,19
CARDIOVASCULAR SYSTEM
Macrolides and quinolones have been reported to cause QT-interval prolongation and torsades de pointes. The risk is greatest when a macrolide is co-administered with a CYP3A4 inhibitor.
Of the macrolides, azithromycin is the safest, as clarithromycin and erythromycin are more likely to cause QT prolongation.
While QT prolongation is a class effect of quinolones, there is variability within the class. Ciprofloxacin is thought to be the safest in terms of cardiovascular adverse effects.20 In addition, Owens and Nolin20 reported that quinolone-associated QT prolongation was more likely to occur in patients with pre-existing QT prolongation, electrolyte abnormalities, organic heart disease, and bradycardia, and especially in women. Other risk factors for QT prolongation with quinolone use include underlying cardiac disease and advanced age.21
Quinolones have also been associated with an increased risk of aortic dissection. The US Food and Drug Administration has issued a warning advising clinicians to avoid quinolones in patients who have aneurysms or are at risk for aneurysms, such as patients with advanced age, peripheral atherosclerotic vascular disease, hypertension and conditions such as Marfan and Ehlers-Danlos syndrome.22
DIGESTIVE SYSTEM
Tetracyclines are known to cause esophagitis from direct contact with and disruption of the mucosal lining. Doxycycline is the most frequent offender.23
Amoxicillin-clavulanate is the antibiotic most commonly associated with drug-induced liver injury, mainly attributable to the clavulanate component.24 It is more common in men over age 50 and with prolonged and repeated dosing and is sometimes fatal. Other adverse effects include Stevens-Johnson syndrome, interstitial nephritis, and thrombotic thrombocytopenic purpura.25
Cholestatic hepatitis has been reported with penicillins, particularly dicloxacillin, oxacillin, and amoxicillin-clavulanate; cephalosporins; doxycycline; sulfamethoxazole-trimethoprim; macrolides; and ciprofloxacin.24–26 Hepatocellular injury is linked to amoxicillin-clavulanate and doxycycline. Drug-induced mixed liver injury has been observed with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim and, rarely, cephalosporins.
Liver injury is classified as cholestatic if the alkaline phosphatase level is more than 2 times higher than normal, or if the ratio of alanine aminotransferase to alkaline phosphatase is less than 2; if the ratio is greater than 5, the injury is considered hepatocellular.24 Mixed liver injury, the most common, is defined as a ratio from 2 to 5.
Nitrofurantoin has also been linked to hepatotoxicity, cirrhosis, and end-stage liver disease, and to death if the drug is continued after the onset of jaundice.26 Death from liver injury has been reported with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and erythromycin, and jaundice indicates a poor prognosis, associated with a 10% mortality rate or need for liver transplant in all patients.24
ENDOCRINE SYSTEM
Clarithromycin, sulfonamides, and quinolones are known to precipitate hypoglycemia by interacting with sulfonylureas. A study of Medicare patients age 66 or older who were taking glipizide or glyburide reported that female sex, older age, and a history of hypoglycemic episodes were associated with antibiotic-related hypoglycemia.27 The odds ratio for hypoglycemia was highest for clarithromycin (3.96), sulfamethoxazole-trimethoprim (2.56), metronidazole (2.11), and ciprofloxacin (1.62) when compared with antibiotics that do not cause hypoglycemia. There was no signal for levofloxacin-mediated hypoglycemia in this series.27
RESPIRATORY SYSTEM
Hypersensitivity lung disease has been reported with penicillin, ampicillin, cephalosporins, ciprofloxacin, and sulfonamides including sulfamethoxazole-trimethoprim.28 The lipopeptide daptomycin has been reported to cause acute eosinophilic pneumonia defined as fever for less than 5 days, pulmonary infiltrates, hypoxemia, and a bronchoalveolar lavage or biopsy study with eosinophils. Daptomycin should be stopped early in these cases, and the patient should not be rechallenged, as the reaction can be deadly.29
Nitrofurantoin has a long history of hypersensitivity pneumonitis in its acute form and a chronic allergic response. While more widely recognized, nitrofurantoin pulmonary toxicity is rare, occurring in 1 in 5,000 patients.30
RENAL SYSTEM
Acute interstitial nephritis has been reported with penicillins, cephalosporins, macrolides, quinolones, sulfonamides, and vancomycin.31–33 Acute tubular necrosis has been linked to cephalosporins and tetracyclines. Crystal nephropathy has been seen with quinolones and sulfonamides.
Advanced age is an important risk factor for renal dysfunction from quinolones,18 and penicillin G has been reported to cause glomerulonephritis.31
MUSCULOSKELETAL SYSTEM
Quinolones have been associated with arthropathy or tendinitis at a rate of 1%, including cases of Achilles tendon rupture.18 The US Food and Drug Administration announced in 2016 that the serious adverse events with fluoroquinolones outweigh the benefits in patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infection, and that they should be used only if there are no other options.34
Daptomycin is known to cause elevations of creatine kinase.34 Weekly monitoring is recommended based on postmarketing data reports of elevations in 2.5% of patients; myopathy is a rarer effect, occurring in 0.2% of patients.35
REPRODUCTIVE SYSTEM
Antibiotics have long been reported to interact with oral contraceptives, but the data are not compelling for commonly used antibiotics. The strongest association is with rifampicin, which reduces oral contraceptive efficacy and warrants an alternative mode of contraception.36
BACK TO OUR PATIENT
Antibiotics can have serious adverse effects, and it is important for clinicians to be cognizant of this. Our 60-year-old patient who was taking cefepime and vancomycin for pneumonia developed prolonged atypical absence seizures. When the cefepime was discontinued, his mental status improved, and no other seizures were observed.
- Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010–2011. JAMA 2016; 315(17):1864–1873. doi:10.1001/jama.2016.4151
- Grill MF, Maganti RK. Neurotoxic effects associated with antibiotic use: management considerations. Br J Clin Pharmacol 2011; 72(3):381–393. doi:10.1111/j.1365-2125.2011.03991.x
- Dakdouki GK, Al-Awar GN. Cefepime-induced encephalopathy. Int J Infect Dis 2004; 8(1):59–61. pmid:14690782
- Bazan JA, Martin SI, Kaye KM. Newer beta-lactam antiobiotics: doripenem, ceftobiprole, and cefepime. Infect Dis Clin North Am 2009; 23(4):983–999. doi:10.1016/j.idc.2009.06.007
- Bandettini di Poggio M, Anfosso S, Audenino D, Primavera A. Clarithromycin-induced neurotoxicity in adults. J Clin Neurosci 2011; 18(3):313–318. doi:10.1016/j.jocn.2010.08.014
- Saidinejad M, Ewald MB, Shannon MW. Transient psychosis in an immune-competent patient after oral trimethoprim-sulfamethoxazole administration. Pediatrics 2005; 115(6):e739–e741. doi:10.1542/peds.2004-1352
- Thomas RJ, Reagan DR. Association of a Tourette-like syndrome with ofloxacin. Ann Pharmacother 1996; 30(2):138–141. doi:10.1177/106002809603000205
- Pharmacia and Upjohn Company LLC. Zyvox® Package Insert. http://labeling.pfizer.com/showlabeling.aspx?id=649. Accessed March 5, 2019.
- Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis 2006; 42(11):1578–1583. doi:10.1086/503839
- Patel K, Green-Hopkins I, Lu S, Tunkel AR. Cerebellar ataxia following prolonged use of metronidazole: case report and literature review. Int J Infect Dis 2008; 12(6):e111–e114. doi:10.1016/j.ijid.2008.03.006
- Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med 2007; 146(9):657–665. pmid:17470834
- Black E, Lau TT, Ensom MH. Vancomycin-induced neutropenia: is it dose- or duration-related? Ann Pharmacother 2011; 45(5):629–638. doi:10.1345/aph.1P583
- Garratty G. Drug-induced immune hemolytic anemia. Hematology Am Soc Hematol Educ Program 2009: 73–79. doi:10.1182/asheducation-2009.1.73
- Chong Bh, Choi PY, Khachigian L, Perdomo J. Drug-induced immune thrombocytopenia. Hematol Oncol Clin North Am 2013; 27(3):521–540. doi:10.1016/j.hoc.2013.02.003
- Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med 2011; 124(7):588–597. doi:10.1016/j.amjmed.2011.01.017
- Chang C, Gershwin ME. Drugs and autoimmunity—a contemporary review and mechanistic approach. J Autoimmun 2010; 34(3):J266–J275. doi:10.1016/j.jaut.2009.11.012
- Kermani TA, Ham EK, Camilleri MJ, Warrington KJ. Polyarteritis nodosa-like vasculitis in association with minocycline use: a single-center case series. Semin Arthritis Rheum 2012; 42(2):213–221. doi:10.1016/j.semarthrit.2012.03.006
- Mandell LA, Ball P, Tillotson G. Antimicrobial safety and tolerability: differences and dilemmas. Clin Infect Dis 2001; 32(suppl 1):S72–S79. doi:10.1086/319379
- Christ W, Esch B. Session III: safety. Adverse reactions to fluoroquinolones in adults and children. Infect Dis Clin Pract 1994; 3(3 suppl 3):S168–S176.
- Owens RC, Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis 2006; 43(12):1603–1611. doi:10.1086/508873
- Rubinstein E, Camm J. Cardiotoxicity of fluoroquinolones. J Antimicrob Chemother 2002; 49(4):593–596. pmid:11909831
- US Food and Drug Administration (FDA). FDA drug safety communication: FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolones antibiotics in certain patients. https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm. Accessed March 15, 2019.
- Seminerio J, McGrath K, Arnold CA, Voltaggio L, Singhi AD. Medication-associated lesions of the GI tract. Gastrointest Endosc 2014; 79(1):140–150. doi:10.1016/j.gie.2013.08.027
- Bjornsson ES, Jonasson JG. Drug-induced cholestasis. Clin Liver Dis 2013; 17(2):191–209. doi:10.1016/j.cld.2012.11.002
- Fontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM. Acute liver failure due to amoxicillin and amoxicillin/clavulanate. Dig Dis Sci 2005; 50(10):1785–1790. doi:10.1007/s10620-005-2938-5
- Sakaan SA, Twilla JD, Usery JB, Winton JC, Self TH. Nitrofurantoin-induced hepatotoxicity: a rare yet serious complication. South Med J 2014; 107(2):107–113. doi:10.1097/SMJ.0000000000000059
- Parekh TM, Raji M, Lin YL, Tan A, Kuo YF, Goodwin JS. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas. JAMA Intern Med 2014; 174(10):1605–1612. doi:10.1001/jamainternmed.2014.3293
- Prasad R, Gupta P, Singh A, Goel N. Drug induced pulmonary parenchymal disease. Drug Discov Ther 2014; 8(6):232–237. doi:10.5582/ddt.2014.01046
- Miller BA, Gray A, Leblanc TW, Sexton DJ, Martin AR, Slama TG. Acute eosinophilic pneumonia secondary to daptomycin: a report of three cases. Clin Infect Dis 2010; 50(11):e63–e68. doi:10.1086/652656
- Kabbara WK, Kordahi MC. Nitrofurantoin-induced pulmonary toxicity: a case report and review of the literature. J Infect Public Health 2015; 8(4):309–313. doi:10.1016/j.jiph.2015.01.007
- Ghane Shahrbaf F, Assadi F. Drug-induced renal disorders. J Renal Inj Prev 2015; 4(3):57–60. doi:10.12861/jrip.2015.12
- Mac K, Chavada R, Paull S, Howlin K, Wong J. Cefepime induced acute interstitial nephritis—a case report. BMC Nephrol 2015; 16:15. doi:10.1186/s12882-015-0004-x
- Woodruff AE, Meaney CJ, Hansen EA, Prescott GM. Azithromycin-induced, biopsy-proven cute interstitial nephritis in an adult successfully treated with low-dose corticosteroids. Pharmacotherapy 2015; 35(11):e169–e174. doi:10.1002/phar.1660
- US Food and Drug Administration (FDA). FDA drug safety communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together. https://www.fda.gov/Drugs/DrugSafety/ucm500143.htm. Accessed March 7, 2019.
- Hawkey PM. Pre-clinical experience with daptomycin. J Antimicrob Chemother 2008; 62(suppl 3):iii7–iii14. doi:10.1093/jac/dkn367
- ACOG Committee on Practice Bulletins–Gynecology. ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol 2006; 107(6):1453–1472. pmid:16738183
A 60-year-old man is admitted for respiratory failure following a massive myocardial infarction. He develops ventilator-associated pneumonia and is treated with cefepime and vancomycin. Three days later, he develops prolonged atypical absence seizures.
What caused these seizures? The neurologist thinks it might be the cefepime. Do you agree?
Antibiotics are widely used in the United States, with 269 million courses of oral therapy prescribed in 2011.1 Adverse effects such as rash are well known, but rare effects such as seizure, hypoglycemia, and hypoxemia may not be immediately attributed to these drugs.
In this article, we review less-recognized but potentially serious adverse effects of antibiotics commonly prescribed in the United States. We have structured our discussion by organ system for ease of reference.
NERVOUS SYSTEM
The potential adverse effects of antibiotics on the nervous system range from encephalopathy and seizure to nonconvulsive status epilepticus.
Encephalopathy and seizure
Encephalopathy has been reported with penicillins, cephalosporins, sulfamethoxazole-trimethoprim, quinolones, and oxazolidinones such as linezolid.2,3
Seizures are known to occur with penicillins, cephalosporins, carbapenems, and quinolones.2–4 For cephalosporins, these effects are more common at higher doses, in elderly patients, and in patients with renal impairment. Carbapenems are associated with seizure activity in elderly patients.2–4
Encephalopathy and seizure can also occur on a continuum, as is the case with piperacillin-induced encephalopathy, with progressive dysarthria, tremor, and progressive confusion culminating in tonic-clonic seizures.2
Nonconvulsive status epilepticus
Nonconvulsive status epilepticus, marked by prolonged atypical absence seizures, has complicated the use of penicillins, quinolones, clarithromycin, and cephalosporins, specifically cefepime.2,3,5 Diagnosis can be difficult and requires clinical awareness and confirmation with electroencephalography.
Class-specific neurologic effects
Certain antibiotics have class-specific effects:
Tetracyclines: cranial nerve toxicity, neuromuscular blockade, and intracranial hypertension.2
Sulfamethoxazole-trimethoprim: tremors and psychosis, with visual and auditory hallucinations.6
Macrolides: dysequilibrium and potentially irreversible hearing loss.2
Quinolones: orofacial dyskinesia and a Tourette-like syndrome, with a higher incidence reported with newer quinolones.7
Linezolid: optic and peripheral neuropathy2; neuropathy can be persistent and can lead to loss of vision. The package insert recommends monitoring visual function in patients taking linezolid for more than 3 months and in any patient reporting visual symptoms.8
Linezolid is also associated with serotonin syndrome when combined with a drug that potentiates serotonergic activity, most commonly selective serotonin reuptake inhibitors. The syndrome is characterized by a triad of cognitive or behavioral changes, autonomic instability, and neuromuscular excitability such as spontaneous clonus.9
Metronidazole: optic and peripheral neuropathy, in addition to cerebellar toxicity and central nervous system lesions on magnetic resonance imaging of the brain. In a series of 11 cases of cerebellar toxicity, most patients presented with ataxia and dysarthria associated with high total doses of metronidazole, and in most cases, magnetic resonance imaging showed resolution of the lesions upon discontinuation of metronidazole.10
HEMATOLOGIC AND RHEUMATOLOGIC EFFECTS
Agranulocytosis has been associated with beta-lactams, in most cases with prolonged exposure. In one report, the average exposure before onset of agranulocytosis was 22 days for nafcillin and 25 days for penicillin. For penicillins, more than 50% of cases involved high daily doses.11
Likewise, most episodes of vancomycin-induced neutropenia were reported to occur after 20 days of therapy.12
In another study, most cases of drug-induced anemia were due to ceftriaxone and piperacillin.13
Drug-induced thrombocytopenia has been described with penicillins, cephalosporins, sulfonamides, and vancomycin14 and is a well-recognized effect of linezolid. The syndrome of drug reaction with eosinophilia and systemic symptoms, a severe and rare adverse reaction, has been reported with minocycline, sulfamethoxazole, and vancomycin.15
The tetracycline minocycline has been reported to cause drug-induced lupus and polyarteritis nodosa-like vasculitis.16 Drug-induced lupus presents as myalgias and arthralgias, serositis, constitutional symptoms, and positive antinuclear antibody titers. The effect is not dose-dependent. Penicillin, cefuroxime, and nitrofurantoin have also been implicated.16
Kermani et al17 described 9 cases of polyarteritis nodosa, in which 5 patients (56%) had systemic involvement including renal artery microaneurysm, mononeuritis multiplex, and mesenteric vasculitis, and some of these patients also had cutaneous involvement. All patients had positive antineutrophil cytoplasmic antibody in a perinuclear pattern. The median time from start of the minocycline to symptom onset was 9 months, and the median duration of use was 2 years.
Quinolones have also been reported to cause fatal hypersensitivity vasculitis.18,19
CARDIOVASCULAR SYSTEM
Macrolides and quinolones have been reported to cause QT-interval prolongation and torsades de pointes. The risk is greatest when a macrolide is co-administered with a CYP3A4 inhibitor.
Of the macrolides, azithromycin is the safest, as clarithromycin and erythromycin are more likely to cause QT prolongation.
While QT prolongation is a class effect of quinolones, there is variability within the class. Ciprofloxacin is thought to be the safest in terms of cardiovascular adverse effects.20 In addition, Owens and Nolin20 reported that quinolone-associated QT prolongation was more likely to occur in patients with pre-existing QT prolongation, electrolyte abnormalities, organic heart disease, and bradycardia, and especially in women. Other risk factors for QT prolongation with quinolone use include underlying cardiac disease and advanced age.21
Quinolones have also been associated with an increased risk of aortic dissection. The US Food and Drug Administration has issued a warning advising clinicians to avoid quinolones in patients who have aneurysms or are at risk for aneurysms, such as patients with advanced age, peripheral atherosclerotic vascular disease, hypertension and conditions such as Marfan and Ehlers-Danlos syndrome.22
DIGESTIVE SYSTEM
Tetracyclines are known to cause esophagitis from direct contact with and disruption of the mucosal lining. Doxycycline is the most frequent offender.23
Amoxicillin-clavulanate is the antibiotic most commonly associated with drug-induced liver injury, mainly attributable to the clavulanate component.24 It is more common in men over age 50 and with prolonged and repeated dosing and is sometimes fatal. Other adverse effects include Stevens-Johnson syndrome, interstitial nephritis, and thrombotic thrombocytopenic purpura.25
Cholestatic hepatitis has been reported with penicillins, particularly dicloxacillin, oxacillin, and amoxicillin-clavulanate; cephalosporins; doxycycline; sulfamethoxazole-trimethoprim; macrolides; and ciprofloxacin.24–26 Hepatocellular injury is linked to amoxicillin-clavulanate and doxycycline. Drug-induced mixed liver injury has been observed with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim and, rarely, cephalosporins.
Liver injury is classified as cholestatic if the alkaline phosphatase level is more than 2 times higher than normal, or if the ratio of alanine aminotransferase to alkaline phosphatase is less than 2; if the ratio is greater than 5, the injury is considered hepatocellular.24 Mixed liver injury, the most common, is defined as a ratio from 2 to 5.
Nitrofurantoin has also been linked to hepatotoxicity, cirrhosis, and end-stage liver disease, and to death if the drug is continued after the onset of jaundice.26 Death from liver injury has been reported with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and erythromycin, and jaundice indicates a poor prognosis, associated with a 10% mortality rate or need for liver transplant in all patients.24
ENDOCRINE SYSTEM
Clarithromycin, sulfonamides, and quinolones are known to precipitate hypoglycemia by interacting with sulfonylureas. A study of Medicare patients age 66 or older who were taking glipizide or glyburide reported that female sex, older age, and a history of hypoglycemic episodes were associated with antibiotic-related hypoglycemia.27 The odds ratio for hypoglycemia was highest for clarithromycin (3.96), sulfamethoxazole-trimethoprim (2.56), metronidazole (2.11), and ciprofloxacin (1.62) when compared with antibiotics that do not cause hypoglycemia. There was no signal for levofloxacin-mediated hypoglycemia in this series.27
RESPIRATORY SYSTEM
Hypersensitivity lung disease has been reported with penicillin, ampicillin, cephalosporins, ciprofloxacin, and sulfonamides including sulfamethoxazole-trimethoprim.28 The lipopeptide daptomycin has been reported to cause acute eosinophilic pneumonia defined as fever for less than 5 days, pulmonary infiltrates, hypoxemia, and a bronchoalveolar lavage or biopsy study with eosinophils. Daptomycin should be stopped early in these cases, and the patient should not be rechallenged, as the reaction can be deadly.29
Nitrofurantoin has a long history of hypersensitivity pneumonitis in its acute form and a chronic allergic response. While more widely recognized, nitrofurantoin pulmonary toxicity is rare, occurring in 1 in 5,000 patients.30
RENAL SYSTEM
Acute interstitial nephritis has been reported with penicillins, cephalosporins, macrolides, quinolones, sulfonamides, and vancomycin.31–33 Acute tubular necrosis has been linked to cephalosporins and tetracyclines. Crystal nephropathy has been seen with quinolones and sulfonamides.
Advanced age is an important risk factor for renal dysfunction from quinolones,18 and penicillin G has been reported to cause glomerulonephritis.31
MUSCULOSKELETAL SYSTEM
Quinolones have been associated with arthropathy or tendinitis at a rate of 1%, including cases of Achilles tendon rupture.18 The US Food and Drug Administration announced in 2016 that the serious adverse events with fluoroquinolones outweigh the benefits in patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infection, and that they should be used only if there are no other options.34
Daptomycin is known to cause elevations of creatine kinase.34 Weekly monitoring is recommended based on postmarketing data reports of elevations in 2.5% of patients; myopathy is a rarer effect, occurring in 0.2% of patients.35
REPRODUCTIVE SYSTEM
Antibiotics have long been reported to interact with oral contraceptives, but the data are not compelling for commonly used antibiotics. The strongest association is with rifampicin, which reduces oral contraceptive efficacy and warrants an alternative mode of contraception.36
BACK TO OUR PATIENT
Antibiotics can have serious adverse effects, and it is important for clinicians to be cognizant of this. Our 60-year-old patient who was taking cefepime and vancomycin for pneumonia developed prolonged atypical absence seizures. When the cefepime was discontinued, his mental status improved, and no other seizures were observed.
A 60-year-old man is admitted for respiratory failure following a massive myocardial infarction. He develops ventilator-associated pneumonia and is treated with cefepime and vancomycin. Three days later, he develops prolonged atypical absence seizures.
What caused these seizures? The neurologist thinks it might be the cefepime. Do you agree?
Antibiotics are widely used in the United States, with 269 million courses of oral therapy prescribed in 2011.1 Adverse effects such as rash are well known, but rare effects such as seizure, hypoglycemia, and hypoxemia may not be immediately attributed to these drugs.
In this article, we review less-recognized but potentially serious adverse effects of antibiotics commonly prescribed in the United States. We have structured our discussion by organ system for ease of reference.
NERVOUS SYSTEM
The potential adverse effects of antibiotics on the nervous system range from encephalopathy and seizure to nonconvulsive status epilepticus.
Encephalopathy and seizure
Encephalopathy has been reported with penicillins, cephalosporins, sulfamethoxazole-trimethoprim, quinolones, and oxazolidinones such as linezolid.2,3
Seizures are known to occur with penicillins, cephalosporins, carbapenems, and quinolones.2–4 For cephalosporins, these effects are more common at higher doses, in elderly patients, and in patients with renal impairment. Carbapenems are associated with seizure activity in elderly patients.2–4
Encephalopathy and seizure can also occur on a continuum, as is the case with piperacillin-induced encephalopathy, with progressive dysarthria, tremor, and progressive confusion culminating in tonic-clonic seizures.2
Nonconvulsive status epilepticus
Nonconvulsive status epilepticus, marked by prolonged atypical absence seizures, has complicated the use of penicillins, quinolones, clarithromycin, and cephalosporins, specifically cefepime.2,3,5 Diagnosis can be difficult and requires clinical awareness and confirmation with electroencephalography.
Class-specific neurologic effects
Certain antibiotics have class-specific effects:
Tetracyclines: cranial nerve toxicity, neuromuscular blockade, and intracranial hypertension.2
Sulfamethoxazole-trimethoprim: tremors and psychosis, with visual and auditory hallucinations.6
Macrolides: dysequilibrium and potentially irreversible hearing loss.2
Quinolones: orofacial dyskinesia and a Tourette-like syndrome, with a higher incidence reported with newer quinolones.7
Linezolid: optic and peripheral neuropathy2; neuropathy can be persistent and can lead to loss of vision. The package insert recommends monitoring visual function in patients taking linezolid for more than 3 months and in any patient reporting visual symptoms.8
Linezolid is also associated with serotonin syndrome when combined with a drug that potentiates serotonergic activity, most commonly selective serotonin reuptake inhibitors. The syndrome is characterized by a triad of cognitive or behavioral changes, autonomic instability, and neuromuscular excitability such as spontaneous clonus.9
Metronidazole: optic and peripheral neuropathy, in addition to cerebellar toxicity and central nervous system lesions on magnetic resonance imaging of the brain. In a series of 11 cases of cerebellar toxicity, most patients presented with ataxia and dysarthria associated with high total doses of metronidazole, and in most cases, magnetic resonance imaging showed resolution of the lesions upon discontinuation of metronidazole.10
HEMATOLOGIC AND RHEUMATOLOGIC EFFECTS
Agranulocytosis has been associated with beta-lactams, in most cases with prolonged exposure. In one report, the average exposure before onset of agranulocytosis was 22 days for nafcillin and 25 days for penicillin. For penicillins, more than 50% of cases involved high daily doses.11
Likewise, most episodes of vancomycin-induced neutropenia were reported to occur after 20 days of therapy.12
In another study, most cases of drug-induced anemia were due to ceftriaxone and piperacillin.13
Drug-induced thrombocytopenia has been described with penicillins, cephalosporins, sulfonamides, and vancomycin14 and is a well-recognized effect of linezolid. The syndrome of drug reaction with eosinophilia and systemic symptoms, a severe and rare adverse reaction, has been reported with minocycline, sulfamethoxazole, and vancomycin.15
The tetracycline minocycline has been reported to cause drug-induced lupus and polyarteritis nodosa-like vasculitis.16 Drug-induced lupus presents as myalgias and arthralgias, serositis, constitutional symptoms, and positive antinuclear antibody titers. The effect is not dose-dependent. Penicillin, cefuroxime, and nitrofurantoin have also been implicated.16
Kermani et al17 described 9 cases of polyarteritis nodosa, in which 5 patients (56%) had systemic involvement including renal artery microaneurysm, mononeuritis multiplex, and mesenteric vasculitis, and some of these patients also had cutaneous involvement. All patients had positive antineutrophil cytoplasmic antibody in a perinuclear pattern. The median time from start of the minocycline to symptom onset was 9 months, and the median duration of use was 2 years.
Quinolones have also been reported to cause fatal hypersensitivity vasculitis.18,19
CARDIOVASCULAR SYSTEM
Macrolides and quinolones have been reported to cause QT-interval prolongation and torsades de pointes. The risk is greatest when a macrolide is co-administered with a CYP3A4 inhibitor.
Of the macrolides, azithromycin is the safest, as clarithromycin and erythromycin are more likely to cause QT prolongation.
While QT prolongation is a class effect of quinolones, there is variability within the class. Ciprofloxacin is thought to be the safest in terms of cardiovascular adverse effects.20 In addition, Owens and Nolin20 reported that quinolone-associated QT prolongation was more likely to occur in patients with pre-existing QT prolongation, electrolyte abnormalities, organic heart disease, and bradycardia, and especially in women. Other risk factors for QT prolongation with quinolone use include underlying cardiac disease and advanced age.21
Quinolones have also been associated with an increased risk of aortic dissection. The US Food and Drug Administration has issued a warning advising clinicians to avoid quinolones in patients who have aneurysms or are at risk for aneurysms, such as patients with advanced age, peripheral atherosclerotic vascular disease, hypertension and conditions such as Marfan and Ehlers-Danlos syndrome.22
DIGESTIVE SYSTEM
Tetracyclines are known to cause esophagitis from direct contact with and disruption of the mucosal lining. Doxycycline is the most frequent offender.23
Amoxicillin-clavulanate is the antibiotic most commonly associated with drug-induced liver injury, mainly attributable to the clavulanate component.24 It is more common in men over age 50 and with prolonged and repeated dosing and is sometimes fatal. Other adverse effects include Stevens-Johnson syndrome, interstitial nephritis, and thrombotic thrombocytopenic purpura.25
Cholestatic hepatitis has been reported with penicillins, particularly dicloxacillin, oxacillin, and amoxicillin-clavulanate; cephalosporins; doxycycline; sulfamethoxazole-trimethoprim; macrolides; and ciprofloxacin.24–26 Hepatocellular injury is linked to amoxicillin-clavulanate and doxycycline. Drug-induced mixed liver injury has been observed with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim and, rarely, cephalosporins.
Liver injury is classified as cholestatic if the alkaline phosphatase level is more than 2 times higher than normal, or if the ratio of alanine aminotransferase to alkaline phosphatase is less than 2; if the ratio is greater than 5, the injury is considered hepatocellular.24 Mixed liver injury, the most common, is defined as a ratio from 2 to 5.
Nitrofurantoin has also been linked to hepatotoxicity, cirrhosis, and end-stage liver disease, and to death if the drug is continued after the onset of jaundice.26 Death from liver injury has been reported with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and erythromycin, and jaundice indicates a poor prognosis, associated with a 10% mortality rate or need for liver transplant in all patients.24
ENDOCRINE SYSTEM
Clarithromycin, sulfonamides, and quinolones are known to precipitate hypoglycemia by interacting with sulfonylureas. A study of Medicare patients age 66 or older who were taking glipizide or glyburide reported that female sex, older age, and a history of hypoglycemic episodes were associated with antibiotic-related hypoglycemia.27 The odds ratio for hypoglycemia was highest for clarithromycin (3.96), sulfamethoxazole-trimethoprim (2.56), metronidazole (2.11), and ciprofloxacin (1.62) when compared with antibiotics that do not cause hypoglycemia. There was no signal for levofloxacin-mediated hypoglycemia in this series.27
RESPIRATORY SYSTEM
Hypersensitivity lung disease has been reported with penicillin, ampicillin, cephalosporins, ciprofloxacin, and sulfonamides including sulfamethoxazole-trimethoprim.28 The lipopeptide daptomycin has been reported to cause acute eosinophilic pneumonia defined as fever for less than 5 days, pulmonary infiltrates, hypoxemia, and a bronchoalveolar lavage or biopsy study with eosinophils. Daptomycin should be stopped early in these cases, and the patient should not be rechallenged, as the reaction can be deadly.29
Nitrofurantoin has a long history of hypersensitivity pneumonitis in its acute form and a chronic allergic response. While more widely recognized, nitrofurantoin pulmonary toxicity is rare, occurring in 1 in 5,000 patients.30
RENAL SYSTEM
Acute interstitial nephritis has been reported with penicillins, cephalosporins, macrolides, quinolones, sulfonamides, and vancomycin.31–33 Acute tubular necrosis has been linked to cephalosporins and tetracyclines. Crystal nephropathy has been seen with quinolones and sulfonamides.
Advanced age is an important risk factor for renal dysfunction from quinolones,18 and penicillin G has been reported to cause glomerulonephritis.31
MUSCULOSKELETAL SYSTEM
Quinolones have been associated with arthropathy or tendinitis at a rate of 1%, including cases of Achilles tendon rupture.18 The US Food and Drug Administration announced in 2016 that the serious adverse events with fluoroquinolones outweigh the benefits in patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infection, and that they should be used only if there are no other options.34
Daptomycin is known to cause elevations of creatine kinase.34 Weekly monitoring is recommended based on postmarketing data reports of elevations in 2.5% of patients; myopathy is a rarer effect, occurring in 0.2% of patients.35
REPRODUCTIVE SYSTEM
Antibiotics have long been reported to interact with oral contraceptives, but the data are not compelling for commonly used antibiotics. The strongest association is with rifampicin, which reduces oral contraceptive efficacy and warrants an alternative mode of contraception.36
BACK TO OUR PATIENT
Antibiotics can have serious adverse effects, and it is important for clinicians to be cognizant of this. Our 60-year-old patient who was taking cefepime and vancomycin for pneumonia developed prolonged atypical absence seizures. When the cefepime was discontinued, his mental status improved, and no other seizures were observed.
- Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010–2011. JAMA 2016; 315(17):1864–1873. doi:10.1001/jama.2016.4151
- Grill MF, Maganti RK. Neurotoxic effects associated with antibiotic use: management considerations. Br J Clin Pharmacol 2011; 72(3):381–393. doi:10.1111/j.1365-2125.2011.03991.x
- Dakdouki GK, Al-Awar GN. Cefepime-induced encephalopathy. Int J Infect Dis 2004; 8(1):59–61. pmid:14690782
- Bazan JA, Martin SI, Kaye KM. Newer beta-lactam antiobiotics: doripenem, ceftobiprole, and cefepime. Infect Dis Clin North Am 2009; 23(4):983–999. doi:10.1016/j.idc.2009.06.007
- Bandettini di Poggio M, Anfosso S, Audenino D, Primavera A. Clarithromycin-induced neurotoxicity in adults. J Clin Neurosci 2011; 18(3):313–318. doi:10.1016/j.jocn.2010.08.014
- Saidinejad M, Ewald MB, Shannon MW. Transient psychosis in an immune-competent patient after oral trimethoprim-sulfamethoxazole administration. Pediatrics 2005; 115(6):e739–e741. doi:10.1542/peds.2004-1352
- Thomas RJ, Reagan DR. Association of a Tourette-like syndrome with ofloxacin. Ann Pharmacother 1996; 30(2):138–141. doi:10.1177/106002809603000205
- Pharmacia and Upjohn Company LLC. Zyvox® Package Insert. http://labeling.pfizer.com/showlabeling.aspx?id=649. Accessed March 5, 2019.
- Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis 2006; 42(11):1578–1583. doi:10.1086/503839
- Patel K, Green-Hopkins I, Lu S, Tunkel AR. Cerebellar ataxia following prolonged use of metronidazole: case report and literature review. Int J Infect Dis 2008; 12(6):e111–e114. doi:10.1016/j.ijid.2008.03.006
- Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med 2007; 146(9):657–665. pmid:17470834
- Black E, Lau TT, Ensom MH. Vancomycin-induced neutropenia: is it dose- or duration-related? Ann Pharmacother 2011; 45(5):629–638. doi:10.1345/aph.1P583
- Garratty G. Drug-induced immune hemolytic anemia. Hematology Am Soc Hematol Educ Program 2009: 73–79. doi:10.1182/asheducation-2009.1.73
- Chong Bh, Choi PY, Khachigian L, Perdomo J. Drug-induced immune thrombocytopenia. Hematol Oncol Clin North Am 2013; 27(3):521–540. doi:10.1016/j.hoc.2013.02.003
- Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med 2011; 124(7):588–597. doi:10.1016/j.amjmed.2011.01.017
- Chang C, Gershwin ME. Drugs and autoimmunity—a contemporary review and mechanistic approach. J Autoimmun 2010; 34(3):J266–J275. doi:10.1016/j.jaut.2009.11.012
- Kermani TA, Ham EK, Camilleri MJ, Warrington KJ. Polyarteritis nodosa-like vasculitis in association with minocycline use: a single-center case series. Semin Arthritis Rheum 2012; 42(2):213–221. doi:10.1016/j.semarthrit.2012.03.006
- Mandell LA, Ball P, Tillotson G. Antimicrobial safety and tolerability: differences and dilemmas. Clin Infect Dis 2001; 32(suppl 1):S72–S79. doi:10.1086/319379
- Christ W, Esch B. Session III: safety. Adverse reactions to fluoroquinolones in adults and children. Infect Dis Clin Pract 1994; 3(3 suppl 3):S168–S176.
- Owens RC, Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis 2006; 43(12):1603–1611. doi:10.1086/508873
- Rubinstein E, Camm J. Cardiotoxicity of fluoroquinolones. J Antimicrob Chemother 2002; 49(4):593–596. pmid:11909831
- US Food and Drug Administration (FDA). FDA drug safety communication: FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolones antibiotics in certain patients. https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm. Accessed March 15, 2019.
- Seminerio J, McGrath K, Arnold CA, Voltaggio L, Singhi AD. Medication-associated lesions of the GI tract. Gastrointest Endosc 2014; 79(1):140–150. doi:10.1016/j.gie.2013.08.027
- Bjornsson ES, Jonasson JG. Drug-induced cholestasis. Clin Liver Dis 2013; 17(2):191–209. doi:10.1016/j.cld.2012.11.002
- Fontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM. Acute liver failure due to amoxicillin and amoxicillin/clavulanate. Dig Dis Sci 2005; 50(10):1785–1790. doi:10.1007/s10620-005-2938-5
- Sakaan SA, Twilla JD, Usery JB, Winton JC, Self TH. Nitrofurantoin-induced hepatotoxicity: a rare yet serious complication. South Med J 2014; 107(2):107–113. doi:10.1097/SMJ.0000000000000059
- Parekh TM, Raji M, Lin YL, Tan A, Kuo YF, Goodwin JS. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas. JAMA Intern Med 2014; 174(10):1605–1612. doi:10.1001/jamainternmed.2014.3293
- Prasad R, Gupta P, Singh A, Goel N. Drug induced pulmonary parenchymal disease. Drug Discov Ther 2014; 8(6):232–237. doi:10.5582/ddt.2014.01046
- Miller BA, Gray A, Leblanc TW, Sexton DJ, Martin AR, Slama TG. Acute eosinophilic pneumonia secondary to daptomycin: a report of three cases. Clin Infect Dis 2010; 50(11):e63–e68. doi:10.1086/652656
- Kabbara WK, Kordahi MC. Nitrofurantoin-induced pulmonary toxicity: a case report and review of the literature. J Infect Public Health 2015; 8(4):309–313. doi:10.1016/j.jiph.2015.01.007
- Ghane Shahrbaf F, Assadi F. Drug-induced renal disorders. J Renal Inj Prev 2015; 4(3):57–60. doi:10.12861/jrip.2015.12
- Mac K, Chavada R, Paull S, Howlin K, Wong J. Cefepime induced acute interstitial nephritis—a case report. BMC Nephrol 2015; 16:15. doi:10.1186/s12882-015-0004-x
- Woodruff AE, Meaney CJ, Hansen EA, Prescott GM. Azithromycin-induced, biopsy-proven cute interstitial nephritis in an adult successfully treated with low-dose corticosteroids. Pharmacotherapy 2015; 35(11):e169–e174. doi:10.1002/phar.1660
- US Food and Drug Administration (FDA). FDA drug safety communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together. https://www.fda.gov/Drugs/DrugSafety/ucm500143.htm. Accessed March 7, 2019.
- Hawkey PM. Pre-clinical experience with daptomycin. J Antimicrob Chemother 2008; 62(suppl 3):iii7–iii14. doi:10.1093/jac/dkn367
- ACOG Committee on Practice Bulletins–Gynecology. ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol 2006; 107(6):1453–1472. pmid:16738183
- Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010–2011. JAMA 2016; 315(17):1864–1873. doi:10.1001/jama.2016.4151
- Grill MF, Maganti RK. Neurotoxic effects associated with antibiotic use: management considerations. Br J Clin Pharmacol 2011; 72(3):381–393. doi:10.1111/j.1365-2125.2011.03991.x
- Dakdouki GK, Al-Awar GN. Cefepime-induced encephalopathy. Int J Infect Dis 2004; 8(1):59–61. pmid:14690782
- Bazan JA, Martin SI, Kaye KM. Newer beta-lactam antiobiotics: doripenem, ceftobiprole, and cefepime. Infect Dis Clin North Am 2009; 23(4):983–999. doi:10.1016/j.idc.2009.06.007
- Bandettini di Poggio M, Anfosso S, Audenino D, Primavera A. Clarithromycin-induced neurotoxicity in adults. J Clin Neurosci 2011; 18(3):313–318. doi:10.1016/j.jocn.2010.08.014
- Saidinejad M, Ewald MB, Shannon MW. Transient psychosis in an immune-competent patient after oral trimethoprim-sulfamethoxazole administration. Pediatrics 2005; 115(6):e739–e741. doi:10.1542/peds.2004-1352
- Thomas RJ, Reagan DR. Association of a Tourette-like syndrome with ofloxacin. Ann Pharmacother 1996; 30(2):138–141. doi:10.1177/106002809603000205
- Pharmacia and Upjohn Company LLC. Zyvox® Package Insert. http://labeling.pfizer.com/showlabeling.aspx?id=649. Accessed March 5, 2019.
- Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis 2006; 42(11):1578–1583. doi:10.1086/503839
- Patel K, Green-Hopkins I, Lu S, Tunkel AR. Cerebellar ataxia following prolonged use of metronidazole: case report and literature review. Int J Infect Dis 2008; 12(6):e111–e114. doi:10.1016/j.ijid.2008.03.006
- Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med 2007; 146(9):657–665. pmid:17470834
- Black E, Lau TT, Ensom MH. Vancomycin-induced neutropenia: is it dose- or duration-related? Ann Pharmacother 2011; 45(5):629–638. doi:10.1345/aph.1P583
- Garratty G. Drug-induced immune hemolytic anemia. Hematology Am Soc Hematol Educ Program 2009: 73–79. doi:10.1182/asheducation-2009.1.73
- Chong Bh, Choi PY, Khachigian L, Perdomo J. Drug-induced immune thrombocytopenia. Hematol Oncol Clin North Am 2013; 27(3):521–540. doi:10.1016/j.hoc.2013.02.003
- Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med 2011; 124(7):588–597. doi:10.1016/j.amjmed.2011.01.017
- Chang C, Gershwin ME. Drugs and autoimmunity—a contemporary review and mechanistic approach. J Autoimmun 2010; 34(3):J266–J275. doi:10.1016/j.jaut.2009.11.012
- Kermani TA, Ham EK, Camilleri MJ, Warrington KJ. Polyarteritis nodosa-like vasculitis in association with minocycline use: a single-center case series. Semin Arthritis Rheum 2012; 42(2):213–221. doi:10.1016/j.semarthrit.2012.03.006
- Mandell LA, Ball P, Tillotson G. Antimicrobial safety and tolerability: differences and dilemmas. Clin Infect Dis 2001; 32(suppl 1):S72–S79. doi:10.1086/319379
- Christ W, Esch B. Session III: safety. Adverse reactions to fluoroquinolones in adults and children. Infect Dis Clin Pract 1994; 3(3 suppl 3):S168–S176.
- Owens RC, Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis 2006; 43(12):1603–1611. doi:10.1086/508873
- Rubinstein E, Camm J. Cardiotoxicity of fluoroquinolones. J Antimicrob Chemother 2002; 49(4):593–596. pmid:11909831
- US Food and Drug Administration (FDA). FDA drug safety communication: FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolones antibiotics in certain patients. https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm. Accessed March 15, 2019.
- Seminerio J, McGrath K, Arnold CA, Voltaggio L, Singhi AD. Medication-associated lesions of the GI tract. Gastrointest Endosc 2014; 79(1):140–150. doi:10.1016/j.gie.2013.08.027
- Bjornsson ES, Jonasson JG. Drug-induced cholestasis. Clin Liver Dis 2013; 17(2):191–209. doi:10.1016/j.cld.2012.11.002
- Fontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM. Acute liver failure due to amoxicillin and amoxicillin/clavulanate. Dig Dis Sci 2005; 50(10):1785–1790. doi:10.1007/s10620-005-2938-5
- Sakaan SA, Twilla JD, Usery JB, Winton JC, Self TH. Nitrofurantoin-induced hepatotoxicity: a rare yet serious complication. South Med J 2014; 107(2):107–113. doi:10.1097/SMJ.0000000000000059
- Parekh TM, Raji M, Lin YL, Tan A, Kuo YF, Goodwin JS. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas. JAMA Intern Med 2014; 174(10):1605–1612. doi:10.1001/jamainternmed.2014.3293
- Prasad R, Gupta P, Singh A, Goel N. Drug induced pulmonary parenchymal disease. Drug Discov Ther 2014; 8(6):232–237. doi:10.5582/ddt.2014.01046
- Miller BA, Gray A, Leblanc TW, Sexton DJ, Martin AR, Slama TG. Acute eosinophilic pneumonia secondary to daptomycin: a report of three cases. Clin Infect Dis 2010; 50(11):e63–e68. doi:10.1086/652656
- Kabbara WK, Kordahi MC. Nitrofurantoin-induced pulmonary toxicity: a case report and review of the literature. J Infect Public Health 2015; 8(4):309–313. doi:10.1016/j.jiph.2015.01.007
- Ghane Shahrbaf F, Assadi F. Drug-induced renal disorders. J Renal Inj Prev 2015; 4(3):57–60. doi:10.12861/jrip.2015.12
- Mac K, Chavada R, Paull S, Howlin K, Wong J. Cefepime induced acute interstitial nephritis—a case report. BMC Nephrol 2015; 16:15. doi:10.1186/s12882-015-0004-x
- Woodruff AE, Meaney CJ, Hansen EA, Prescott GM. Azithromycin-induced, biopsy-proven cute interstitial nephritis in an adult successfully treated with low-dose corticosteroids. Pharmacotherapy 2015; 35(11):e169–e174. doi:10.1002/phar.1660
- US Food and Drug Administration (FDA). FDA drug safety communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together. https://www.fda.gov/Drugs/DrugSafety/ucm500143.htm. Accessed March 7, 2019.
- Hawkey PM. Pre-clinical experience with daptomycin. J Antimicrob Chemother 2008; 62(suppl 3):iii7–iii14. doi:10.1093/jac/dkn367
- ACOG Committee on Practice Bulletins–Gynecology. ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol 2006; 107(6):1453–1472. pmid:16738183
KEY POINTS
- Piperacillin-induced encephalopathy and seizure can occur on a continuum, with progressive dysarthria, tremor, and confusion culminating in tonic-clonic seizures.
- Monocycline-induced lupus can present as myalgia, arthralgia, serositis, constitutional symptoms, and a positive antinuclear antibody titer. The effect is not dose-dependent.
- Acute tubular necrosis has been linked to cephalosporins and tetracyclines. Crystal nephropathy has been reported with quinolones and sulfonamides.
- QT-interval prolongation is a class effect of quinolones and is more likely to occur in patients with pre-existing QT prolongation, electrolyte abnormalities, organic heart disease, or bradycardia, or in women.
